Thursday, 22 March 2012

Guest Post: Prof George Ebers

Dear Prof Ebers
You have been given star billing by people proporting the CCSVI lobby as a person who is not tainited by the pharma industry and are happy to report that


One of the bloggers asked "Are his comments regarding flawed outcome measures for DMDs, proof against using DMDs? The CCSVI activists certainly think so"

I was wondering if you had any time to write a post for our MS blog site on the above for lay people. Maybe you could pass comment on whether the same holds true, post the active immunosuppressives like tysabri. 



Prof Ebers Wrote

"David Baker kindly sent me some comments attributed to me to which I have pleasure in replying.

The comments are slightly out of context coming from a debate where I was taking the polarised side of there being major doubts about the outcomes used in MS trials. This is not a matter of opinion really since they have been subjected to careful study by the Sylvia Lawry Centre in Munich using results from some 40 trials, and have also been carefully evaluated in our studies on the natural history of MS where approx. 1000 patients were followed untreated for nearly 30 years on average. This population evaded so-called disease-modifying drugs as accrual ended in 1984 and by the time they were being promoted they were either too disabled to be considered or had done too well to want them.

In the first instance relapses were unrelated to long term outcome and surely no study should now be published with this as the outcome nor should studies be done in which patients are subjected to risk where this is the primary outcome. It is clearly unethical by consensus criteria, which reasonably insist that the outcomes have to be meaningful for risk to be taken on, otherwise no result of value to patients can come out of such trials. This result is supported by there being little from long term followup of the original treatment trials to indicate that relapses are a meaningful indicator of treatment effect when long term disability is considered. After all Long Term disability is the overwhelming medical social and economic impact of MS.

When the Sylvia Lawry results became apparent the response of the International Federation of MS Societies was to withdraw their funding. As contrary to the goals of MS patients and families this might have been, the following points need be made:

1) It was the only databank capable of assessing the results of all clinical trials leading to drug approval at the time and the only one with the raw data – only the placebo arms

2) Contrary to consensus recommendations by journals, almost all the large studies had been carried out with the investigators never having been given the raw data

3) The pharmaco-economics data from Scharr leading to the UK risk-sharing scheme had shown the outcomes were flimsy at best.

So I stand by what I said in the debate but rather than saying the outcomes are worthless it seems more appropriate to say they have not been validated. Frankly this is damning enough and if patients have been promised benefit in the long term, this is overstating the evidence.

Turning to disability, it was clear from the Sylvia Lawry Centre analyses that the definitions used for disability in the trials could not be validated either.

The response of the companies in general was to ignore these findings and continue to execute studies using unvalidated outcomes primarily because they were outcomes they knew they could beat. The Lancet has published several studies using unvalidated outcomes having had its industry funded reviewers reject the papers clearly showing these outcomes have little meaning in the context of the real disability patients fear.

If anyone wants the primary documents showing the flimsiness of the trial outcomes then please have someone who is prepared to distribute them email me for copies of the key papers, almost all of which have attracted editorial commentary, something indicating the editors thought them important.

I think the lesson from CCSVI which cannot be ignored is that the price of losing confidence in the medical system can be great and damaging on both sides of this debate. Physicians who are mystified by all this should keep this obvious conclusion in mind.

Best wishes

Prof GC Ebers

University of Oxford"


Sylvia Lawry founded the US National MS society USA in 1946 and by 1967 the worldwide Multiple Sclerosis International Federation (MSIF) with headquarters in London. The Sylvia Lawry Centre is a repository for clinical trial placebo data, because at some stage it will not be ethical to do any placebo arm to trials, when you have active drugs.

56 comments:

  1. On this blog Prof G says he hopes that effective drugs will help in the long term. Nobody has 'promised benefit in the long term'.

    "Long Term disability is the overwhelming medical social and economic impact of MS."
    -True, long term disability is what makes MS so bad. But relapses also matter. My daughter is a case of paediatric MS. The way things were before a DMD, she could not have continued with school. At that time the neurologists just wanted to get her stable. It's been five years and there have been many problems and ups and downs. But she hasn't had to drop out and has a near normal life. I think that is benefit enough.

    Thanks to the internet I am part of a large group of parents of kids/teens with MS. Tysabri has been a life-saver for many. The risks are high and it is always a difficult decision to put a child on Tysabri, Fingolimod, etc. But the kids had so many problems that parents decided the risk was worth taking.

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  2. Not sure if this answers question, if this is proof against DMD?

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  3. "The Lancet has published several studies using unvalidated outcomes having had its industry funded reviewers reject the papers clearly showing these outcomes have little meaning in the context of the real disability patients fear."

    Hard statement. "Self preservation of pharma industry" is the term that freely comes in mind. Others may prefer "conspiracy".

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  4. Challenging stuff if the achievement of reduced long-term disability is the sole goal of treatment. Personally, if it's going to happen anyway I think I'll go for the option of fewer relapses before I get there. Is there any research happening that looks at the effect of CCSVI long-term disability?

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  5. The thing is no-one has done long term follow up studies on the latest DMTs and any influence of the slowing of disability (though early indications with early use of alemtuzumab hints at this).
    All the data that people use to dismiss DMTs is based on drugs like Inetrferon beta which are at best modestly effective in the reduction of relapses comapared to the current drugs like Tysabri, Alemtuzumab anf Gilenya.
    Long-term follow up studies need to be performed to see if the more effective suppression of relapses can have a significant effect on disability progression.
    In my view anything that significantly reduces relapses should have an effect on progression but it won't be the whole story and progression may grumble on but perhaps at a slower rate, which is why my research interest is the development of neuroprotective agents which used in conjunction with DMts hopefully will greatly slow the degenerative process that drives disability.

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  6. Strange, no reaction to statements as the following:

    "In the first instance relapses were unrelated to long term outcome and surely no study should now be published with this as the outcome nor should studies be done in which patients are subjected to risk where this is the primary outcome."

    In other words all these new-age, hi-tech, low-relapse bio-drugs are not properly validated in order to be considered effective. I would expect some strong counter-argument from this blog, not just "in my opinion lesions & relapses count".

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  7. Reactions from Whom?

    We and you have had enough reactions in the past few days.

    You can read this and the other posts and formulate your opinion as Keith Richards said.......SLAP.

    Tell the people who get disabled by a relapse that they do not count. Think about it.

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  8. Re: "I would expect some strong counter-argument from this blog, not just "in my opinion lesions & relapses count"

    Interestingly, several publications have now shown that MSers on DMTs who continue to relapse and/or acquire new MRI lesions do very badly in terms of future disability progression. In other words ongoing relapses or MRI activity are a good marker or non-response. It would take a brave neurologist, and a brave MSer, to take ignore this data. In addition, DMTs are expensive why continue treating someone with an ineffective drug?

    The problem is that the average effect of DMTs may be modest, but in individual MSers the response can be very good. What has been ignored up until now is the observation that some MSers respond very well (disease-activity free). Why deny the responders active treatment when the average effect is modest? The same debate has happened in the oncology field; it is clear that some tumours are more responsive to certain chemotherapy regimens than others. The new challenge is identifying the people accurately. This emerging field is called PERSONALISED MEDICINE, I have embraced the field and have started actively monitoring for responders and non-responders. It is the least I can do.

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  9. Prof Ebers seems to say
    1. the only outcome worth bothering about in MS is the prevention of long term disability
    2. testing drugs carries risks and as their efficacy on the prevention of long term disability is unproven, it shouldn't be done
    3. testing drugs carries risks, and their efficacy on reducing relapses doesn't matter as relapses are unrelated to long term outcome (as shown by the untreated 1000 patients over 30 years presumably?)
    Are these conclusions right about what he is saying, or have I got the wrong end of the stick?

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  10. "In other words all these new-age, hi-tech, low-relapse bio-drugs are not properly validated in order to be considered effective."

    As the time to progress to development to disability can take years if not decades, you would need a time machine to properly validate the new DMTs and their effect on progression. I suggest that many MS patients cannot afford to wait until the validation is performed to your rigorous criteria.

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  11. This comment has been removed by the author.

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  12. MD2,

    "I suggest that many MS patients cannot afford to wait until the validation is performed to your rigorous criteria."

    That's exactly what they would say to you on the venoplasty table.

    "you would need a time machine to properly validate the new DMTs and their effect on progression."

    That means it is URGENT to find proper prognostic markers of long term disability, instead of deleting lesions on MRI.

    MD,

    "Tell the people who get disabled by a relapse that they do not count. Think about it."

    I don't have to think about it. I have experienced it. I am sure prof Ebers has thought about it a lot before making this statement.

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  13. VV,
    The drugs have gone through multi-phase multi-year trials and have AT LEAST proved to be effective for relapses.
    The blinded venoplasty trials are still happening and nothing has been proven yet.
    Venoplasty trials won't conform to Prof Ebers' criteria either. For that you will have to wait many many years. So do you want these trials to stop? Are you sure you want to follow his criteria?

    Re 'it is URGENT to find proper prognostic markers of long term disability' - agree

    Re 'instead of deleting lesions on MRI' - do not agree. Lesions on MRI are good enough till better markers are found

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    Replies
    1. Though I hesitate to tell any MSer what to do, I would caution against spending your money on CCSVI treatment as the more studies that report, the more the evidence accumulates that is a waste of time (and money) at best.

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  14. Re "some MSers respond very well (disease-activity free)"

    Even more information is hidden in the group of patients that completely fail to respond to any therapy. Extensive, parallel investigation of both extreme groups seems to be a prospective way to learn more about MS.

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  15. Roshni,

    it's too early for blinded, placebo-controlled venoplasty studies to take place. The reason is that there is still no consensus about what should be treated and how. However, one trial of that kind has just commenced, BRAVE DREAMS.

    What should be done now is extensive research studies with the collaboration of neurologists. The preliminary results show evidence that long believed MS symptoms are not at all consequences of CNS damage. This opens a window for new markers of MS progression, and redraws the face of MS in a way that makes your questions a bit out of focus.

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  16. it's too early for blinded, placebo-controlled venoplasty studies to take place

    Then why have MS Societies been pressurised to investigate and fund just this?

    There is no consensus between who? Schelling and Zamboni?

    What should be done now is collaboration with Neuros.

    Who are the other collaborators?

    I don't have to think about it. I have experienced it.

    So relapses are of no consequence in your opinion? If not then I would be better not to have then right?

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  17. Sorry terrible spelling
    Then it would be better not to have them right?

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  18. You leave me dumbfounded VV. Your response makes no sense (not to me anyway)

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  19. Re "Then why have MS Societies been pressurised to investigate and fund just this?"

    Partly because of the pressure from neurologists for data from that kind of studies.

    Re "There is no consensus between who? Schelling and Zamboni?"

    Between IRs. For example, everybody agree that internal jugulars, azygos and lumbar veins are critical. But some see a role for the left renal vein also.
    Furthermore, to stent or not to stent? What is the optimal balloon size? What is the best post operative anticoagulation scheme? Should IVUS be used?

    All these questions and more need to be answered before designing a treatment protocol of maximum efficiency. Until this goal is met, it won't be clear whether a procedure failed or whether the diagnosis/treatment were simply incomplete.

    Re "So relapses are of no consequence in your opinion? "

    I 've told you before that they seem to be an epiphenomenon of the damaging process, not the damaging process itself. Wiping them out by medication may ease a patients experience but certainly won't have an impact on their cause. Tangling with the immune system is unwise and dangerous, unless there is irrefutable proof that it is the one to blame for ALL the damages in MS.

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  20. Using this logic, pain incontinence, spasticity would also be epiphenomenon and should not be treated..as this has no impact on the cause...I do not agree.

    All these questions and more need answering..... Surely if it is a bust there is not point spending more time fine tuning. Show it works and then you can fine tune.

    You appear to believe that CCSVI trials will not work! Should we stop donating to Brave dreams?

    It is suggestive that if the studies do not give you the right answer you will not believe it!

    http://multiple-sclerosis-research.blogspot.co.uk/2012/01/what-is-your-story.html

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  21. "pain incontinence, spasticity"

    These are neurological deficits that result from CNS damage. During its evolution the damaging process may had some abrupt moments that were signed by a relapse. In that way, relapses don't matter. But it's clear that the deficits themselves need treatment, especially if they are permanent.

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  22. "Show it works and then you can fine tune."

    Fine tuning is not only about maximizing efficacy, but also about minimizing risks, like thrombosis. Remember that the whole idea is about keeping the veins patent. If an incomplete procedure reduced vein patency, then it could result in ccsvi deterioration and totally negative results.

    From personal experience, the first treating IR missed the main problem and chose to treat what the second never would.

    I trust that IRs in BRAVE DREAMS have adequate experience and their treatment protocol is a conservative one.

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  23. Relapses don't matter.

    http://multiple-sclerosis-research.blogspot.co.uk/2012/01/what-is-your-story.html

    What does IR mean?

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  24. Re "What does IR mean?"

    Interventional Radiologist

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  25. If news from the Interventinol radiologist meeting (www.msrc.co.uk)about success of 75% efficacy in unblinded study of 180 MSers pans out it should be easy to show an effect?

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  26. Sad to see people who have had a good response to CCSVI still being labelled here as 'activists' because they dare to speak of their support.

    "Show it works and then you can fine tune"
    CCSVI has been shown to work in many many people, some of whom you have met.
    "Why deny the responders active treatment when the average effect is modest?"
    Surely then GG this rule should apply in the case of CCSVI treatment especially as the average effect is far from modest?

    Glad to see Prof. Ebers response, some good valid facts, as expected.

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    1. Re: "CCSVI has been shown to work in many many people, some of whom you have met."

      There is no class 1 & 2 evidence that it works. That is the problem. Until we have the results of randomised double-blind controlled trials of sham procedures all we can say is the evidence is weak.

      When people have tried to confirm the findings of others they have problems diagnosing this condition, i.e. they can't find the stenoses that Zamboni found if they do find them they are no more common in MS compared to other conditions. How can you treat a condition you can't find, or is non-specific? The fact that a large number of neuroradiologists in private facilities find and treat CCSVI, often against the recommendations of national guidelines, is worrying; particularly as they are being paid. We need to wait the outcome of the clinical trials. Nobody should be having to pay for any procedure aimed at treating CCSVI until we have evidence that it works.

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    2. ALL the negative studies on ccsvi have been reported by neurologists who have zero experience in vascular issues or are being done by people with serious conflicting interests.
      You know this GG, it doesn't take a genius to see whats being reported is not in anyway fair or unbiased, or if not as the uk's leading MS researchers you should.
      Still you continue to fall back on, settle for and worse still stand by these sorry findings and instead of turning your attention to it to finding the truth you secure your own future with another DNA study (replicating what has already been done in the US) that is doing nothing to help people here and now.
      Please stop trying to drag this down by keep mentioning that people are having to pay, they are only having to pay because they are being failed by others who are looking out for their own interests.

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    3. ALL the positive studies on CCSVI seem to have been reported by people who have serious conflicting interests, which in many cases are not declared. People are having to pay because in my opinion they are being duped by those with vested interests.
      What you don't realise is that if this really was the wonder cure that some suggest and there was HARD unbiased evidence for the procedure, there would be none more happy than us. But closer examination suggests it isn't so we aren't.

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    4. There is no evidence of a conspiracy. Why should there be? We all want as much as you for MSers to be cured or made better. We also have a responsibility to protect them from Charlatans and from harm. The treatments for CCSVI are not without risks; some people have died after undergoing the procedure!

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    5. GG, not as many have died from CCSVI treatment (3 maybe 4 depending on how you judge it) as from Tysabri induced PML (70 to date). There are risks in any medical treatment, it is a matter of evaluating risk versus benefit and the patient should be able to have a say in how much risk s/he is prepared to accept. If we are to tailor treatment to the patient then clinical trials have very little relevance to the validity of CCSVI as a treatment for an individual.
      In my opinion it is important to use terms correctly: could we all take care to not call "CCSVI" the treatment, it is the condition. The treatment is venoplasty which is a safe procedure carried out in our hospital daily. The risks of CCSVI venoplasty treatment is even lower in people with the MS diagnosis than it is in other patient. The NHS states that the acceptable fatality rate is 1% (1 in 100) in venoplasty treatment, in the case of CCSVI venoplasty the incidence of death is about 1 in 10,000.

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  27. "Show it works and then you can fine tune"

    The analogy I've heard is of the trials that were done when carotid stenting was first begun. Carotid stenting done by inexperienced practitioners since it was a new technique was compared to open vascular surgery done by experienced practitioners. Carotid stenting fared poorly in comparison but the techniques have since been improved. Lots of controversy and wasted time.

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  28. -"The treatments for CCSVI are not without risks; some people have died after undergoing the procedure!"

    323/70. Of course it was all patients fault, since they made an informed decision. PML/Deaths on Tysabri.

    -"There is no evidence of a conspiracy."

    What does conspiracy look like to you? Working for companies who bribe doctors to sell drugs isn't much of an evidence?

    -"Why should there be?"

    Because Biogen and Elan stock holders are more worried about PML that doctors who prescribe Tysabri.

    -"There is no class 1 & 2 evidence that it works."

    You perpetuate a constant confusion regarding CCSVI. CCSVI treatment is only the conclusion of an evolving theory to explain the origin of MS. You expect evidence to come only from trials because you are accustomed to that way of (drug) research. You never, never got in to trouble of seriously examining how the new theory could explain certain mysteries of the disease. CCSVI treatment is far from being perfected, so these trials will inevitably incorporate the treatment weaknesses. Without diving into the CCSVI theory and testing it in other possible ways you will end up drawing wrong conclusions.

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  29. "You expect evidence to come only from trials because you are accustomed to that way of (drug) research."

    So previously you were asking for clinical trials/research on CCSVI yet now they are being done and the gathering evidence disagrees with your views its the clinical trials paradigms fault. Presumably in VV world the regulators should be listening to you rather than qualified professionals. Fortunately the real world still seems to hold sway.

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    1. To put it even more simply: There is only one way to give a pill, but a million ways to perform an angioplasty.

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    2. But whether you should be performing an angioplasty is another matter entirely.

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    3. "in the case of CCSVI venoplasty the incidence of death is about 1 in 10,000"; that is higher than the risk of getting PML if you are JCV-ve on Tysabri! Interesting?

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    4. "There is only one way to give a pill"...not when its a suppository? The preferred route for an aspirin for some :-)

      A million ways to perform an angioplasty,...for money appears to be the commonest way how simple is that?

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  30. VV, the difference between the risk of tysabri and the risk of CCSVI treatment is that the risks and benefits are known in Tysabri. Any procedure in which risks are known and benefit is unknown warrants caution.

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    1. As we can see from the recent Italian study adverse effects were about 3%

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    2. Maren, what exactly are the benefits of Tysabri?
      The real difference between the two approaches is that the CCSVI treatment respects the fundamentals regarding periventricular lesion formation in the brain, and the longitudinal lesion distribution in the spine. Tysabri aims at T-cells that just drive post-traumatic inflammation.

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    3. The benefits of Tysabri are it greatly reduces new lesion formation.

      "Tysabri aims at T-cells that just drive post-traumatic inflammation."

      And what exactly would this "trauma" be exactly? Perhaps it's induced after reading one of your posts? It certainly isn't being driven by venous insufficiency.

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    4. Tysabri warrants caution too because of the severity of the adverse event (PML) if it happens. What Tysabri has that CCSVI treatment lacks is that it's been fully researched. As the research comes in on CCSVI treatment, the risks and benefits will be clarified.

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  31. To the poster who is disgruntled that posts have been deleted, we really don't go in for naming names on the blog otherwise it gets too personal etc.

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  32. OK, that makes sense but perhaps you should not have published his/her post to begin with, as now I'm wondering what was meant that lesions are not a marker 'in anyway' for MS. I don't understand why this would be the case.

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    Replies
    1. It was my mistake in allowing the comment.
      I'm wondering exactly what was meant by that comment re lesions and MS too.

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  33. Vanishing comments...... It is not appropriate to be naming neuros in comments and posts should not have been launched. The neuro may not read the blog and so will not comment on their side of the story

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    1. Furthermore, comments that may defame people or their integrity will only hasten cessation of the ability to post comment or even the closure of the blog....This is a real possibility. It is not about distrust.

      We are busy people and do not have time to run this blog by committee. So we make mistakes, we don't always have time to edit of redact posts.

      The comments could have been made without naming people and then maybe answers could have been forthcoming

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  34. Perhaps you can put some posting guidance up as a stickie or as an additional item in the top menu bar. This may avoid this coming up again in the future. I'd still like to know what the poster meant when he/she posted that 'name-not-to-be-said neurologist stated that lesions are in 'not in any way a marker for MS'. It could be that this was misunderstood, it could be that it was incorrectly written. It could be I will never know ...

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    1. Whats this all about"

      So Anon wrote (paraphrased) "My neurologist stated to me that lesions are not in ANYway a marker for MS and the only way a person can tell if the drug is working was the amount of relapses they were getting".

      I think the neuro was talking out of the wrong hole...if they are suggesting that MRI (talking about gadolinium enhancing lesions here) does not indicate active MS. If you have gadolinium enhancing lesions your MS is active.

      However does the level of gadolinium enhancing lesion equate to relapse activity...not necessarily and does it equate to disability...not necessarily however are they related very likely yes. The more relapses you have in early in disease the more likely you will be disabled however one relapse due to a lesion in the certain places can be catastrophic.

      However MRI does not tell you what is going to happen not necessarily...Natalizuimab gets rid of MRI lesions more or less and gets rid of relapse. Beta interferons get rid of MRI lesions but are not great on relapses, copaxone isn't great at getting rid of MRI lesions. So is this what was being said? That MRI is not a precise crystal ball.


      Anon said "Regarding long term disability I am now disabled after 20 odd years since dx and have a 20+ hours a week carer to assist. First 15 years done very well with no meds then I relapsed and was put on Copaxone and things worked for short time then got much worse so I quit taking the drugs".

      So now here is an example of do nothing and disability develops many years later. This to mean argues against the wai tand do nothing approach. This is why we argue treat to NEDA

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    2. "Perhaps you can put some posting guidance up as a stickie or as an additional item in the top menu bar".

      I suspect people will not read it. However there is no harm trying

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    3. Thanks MouseDoctor, I see the light on the lesions comment now. This is the problem with some neurologists, the one whose name we cannot speak, turned me down for a DMT in 2003 with the words 'these drugs are for sick people, you are not sick, my dear. It's not always the patient who is in denial with MS.

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    4. There are the "wait and see" bridage an the "lets kick some butt" brigade when it comes to MS and because all drugs come with side effects, choice it is a effect:side effect balance that comes into play.

      With the increasing number of choices available the "wait and see" are going to find itharderandharder not to engage

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  35. thank you for providing solutions to problems that I experienced, I hope you can continue to write helpful articles dedicated more

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